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3 Aminobenzamide
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Csaba Szabo – One of the best experts on this subject based on the ideXlab platform.
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Suppression of poly (ADP-ribose) polymerase activation by 3–Aminobenzamide in a rat model of myocardial infarction : long-term morphological and functional consequences
British journal of pharmacology, 2001Co-Authors: Lucas Liaudet, László Virág, Éva Szabó, Leonid Timashpolsky, Attila Cziráki, Csaba SzaboAbstract:1 Recent studies demonstrated that inhibition or genetic inactivation of the enzyme poly (ADPribose) polymerase (PARP) is beneficial in myocardial reperfusion injury. PARP activation in the reperfused myocardium has been assumed, but not directly demonstrated. Furthermore, the issue whether pharmacological PARP inhibition aAords long-term functional benefit in the reperfused myocardium has not been explored. These questions were addressed in the present study. 2 In a rat model of myocardial ischemia (1 h) and reperfusion (up to 24 h), there was a marked and significant activation of PARP in the ischemic borderzone, as determined by poly(ADP-ribose) (PAR) immunohistochemistry. PAR localized to the nuclei of myocytes and infiltrating mononuclear cells. In the core of the infarction, necrotic tissues and diAuse PAR staining were observed. PARP activation remained markedly detectable 24 h after reperfusion. The PARP inhiinhibitor 3Aminobenzamide (20 mg kg 71 intraperitoneally 10 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced the activation of the enzyme in myocytes. 3 3–Aminobenzamide significantly protected against myocardial morphological and functional alterations at 24 h post-reperfusion. Notably, infarct size was reduced, circulating creatine kinase activity was attenuated, and myocardial contractility (dP dt 71 ) was restored by 3–Aminobenzamide. 4 Our results demonstrate a significant and prolonged activation of PARP in the reperfused myocardium, localizing to the necrotic area and the ischaemic borderzone. Furthermore, the studies demonstrate that PARP inhibition aAords long-term beneficial morphological and functional eAects in the reperfused myocardium. These data strengthen the notion that pharmacological PARP inhibition is a viable novel experimental approach for protection against myocardial reperfusion injury. British Journal of Pharmacology (2001) 133, 1424‐1430
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Protective effects of 3–Aminobenzamide, an inhibitor of poly (ADP-ribose) synthase in a carrageenan-induced model of local inflammation
European journal of pharmacology, 1998Co-Authors: Salvatore Cuzzocrea, Basilia Zingarelli, Andrew L Salzman, Eli Gilad, Paul W. Hake, Csaba SzaboAbstract:Abstract A cytotoxic cycle triggered by oxidant-induced DNA single strand breakage and subsequent activation of the nuclear enzyme poly (ADP-ribose) synthetase have been shown to contribute to the cellular injury during various forms of oxidant stress in vitro. The aim of the present study was to investigate the role of poly (ADP-ribose) synthetase in a model of acute local inflammation (carrageenan-induced pleurisy), where oxyradicals, nitric oxide and peroxynitrite are known to play a crucial role in the inflammatory process. The results show that the poly (ADP-ribose) synthetase inhibitor 3–Aminobenzamide (given at 1–30 mg/kg) inhibits the inflammatory response (pleural exudate formation, mononuclear cell infiltration, histological injury). Moreover, 3–Aminobenzamide reduces the formation of nitrotyrosine, an indicator of the formation of peroxynitrite, in the lung. The present results demonstrate that 3–Aminobenzamide, presumably by inhibition of poly (ADP-ribose) synthetase, exerts potent anti-inflammatory effects. Part of the anti-inflammatory effects of 3–Aminobenzamide may be related to a reduction of neutrophil recruitment into the inflammatory site.
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protection against myocardial ischemia and reperfusion injury by 3 Aminobenzamide an inhibitor of poly adp ribose synthetase
Cardiovascular Research, 1997Co-Authors: Basilia Zingarelli, Salvatore Cuzzocrea, Zsuzsanna K Zsengeller, Andrew L Salzman, Csaba SzaboAbstract:Objective: Peroxynitrite and hydroxyl radical, reactive oxidants produced during reperfusion, are potent triggers of DNA single strand breakage. DNA injury triggers the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), which contributes to cellular energetic depletion. Using 3–Aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of myocardial reperfusion injury in a rat model. Methods and results: Occlusion of the left main coronary artery (one hour) followed by reperfusion (one hour) in the anesthetized rat caused severe cardiac necrosis, neutrophil infiltration, and increased plasma creatine phosphokinase activity. There was significant peroxynitrite production during reperfusion, as indicated by a massive increase in nitrotyrosine in the necrotic myocardium. Reperfusion was also associated with a significant loss of myocardial ATP. In vivo administration of the PARS inhibitor 3–Aminobenzamide (10 mg/kg i.v.) to rats subjected to myocardial ischemia and reperfusion, reduced myocardial infarct size and blunted the increase in plasma creatine phosphokinase activity and myeloperoxidase activity in infarcted hearts. In addition, 3–Aminobenzamide partially preserved the myocardial ATP levels. In vitro, pharmacological inhibition of PARS also ameliorated peroxynitrite-induced cytotoxicity in rat cardiac myocmyocytes and human endothelial cells. Conclusion : 3–Aminobenzamide has significant protective effects in myocardial reperfusion injury. We hypothesize that activation of PARS activation plays a role in the pathophysiology of acute myocardial infainfarction.
Helmuth Hilz – One of the best experts on this subject based on the ideXlab platform.
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3‐Aminobenzamide inhibits cytotoxicity and adhesion of phorbol‐ester‐stimulated granulocytes to fibroblast monolayer cultures
European journal of biochemistry, 1991Co-Authors: Thomas Meyer, Helgard Lengyel, Werner Fanick, Helmuth HilzAbstract:Damage of 3T3 fibroblasts as induced by short-term co-cultivation with O2(-)-producing granulocytes, stimulated by 12-O-tetradecanoyl-phorbol-13–acetate (TPA), was compared with that induced by treatment with enzymically generated O2- and with the alkylating agent dimethyl sulfate. The action of stimulated granulocytes was different in several aspects: (a) DNA fragmented by the products of TPA-stimulated granulocytes showed a biphasic alkaline elution pattern while fragmentation induced by alkylation or by enzymically produced O2- was monophasic. (b) Poly(ADP-ribosyl)ation of nuclear proteins after treatment with TPA-stimulated granulocytes exhibited a lag phase and was, in most experiments, less pronounced than after equitoxic dimethyl sulfate treatment. (c) 3–Aminobenzamide, the most widely used inhibitor of ADP-ribosylation, partially protected target cells from the cytotoxic effects of TPA-stimulated granulocytes, while it enhanced alkylation-induced and O2(-)-induced cytotoxicity. Protection by 3–Aminobenzamide in the granulocyte system was apparently not mediated by an inhibition of nuclear poly(ADP-ribosyl)ation. Other inhibitors, like benzamide and nicotinamide, augmented cytotoxicity of TPA-stimulated granulocytes. The unique effect of 3–Aminobenzamide in this system appeared to relate to TPA-induced adhesion of the neutrophils to surfaces. In the presence of 1 mM 3–Aminobenzamide, but not of benzamide, the adhesion of stimulated granulocytes to 3T3 monolayer cultures was markedly reduced or even abolished. This effect was also seen in granulocyte preparations depleted of monocytes. Since 3–Aminobenzamide at the doses applied does not inhibit TPA-induced superoxide production in isolated granulocytes, its specific anticytotoxic effect appears to result from a ‘dilution’ of granulocyte-derived damaging agents into the medium. Our data suggest that prevention of granulocyte adhesion is likely to reduce tissue damage and carcinogenesis in areas of chronic inflinflammation.
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3 Aminobenzamide inhibits cytotoxicity and adhesion of phorbol ester stimulated granulocytes to fibroblast monolayer cultures
FEBS Journal, 1991Co-Authors: Thomas Meyer, Helgard Lengyel, Werner Fanick, Helmuth HilzAbstract:Damage of 3T3 fibroblasts as induced by short-term co-cultivation with O2(-)-producing granulocytes, stimulated by 12-O-tetradecanoyl-phorbol-13–acetate (TPA), was compared with that induced by treatment with enzymically generated O2- and with the alkylating agent dimethyl sulfate. The action of stimulated granulocytes was different in several aspects: (a) DNA fragmented by the products of TPA-stimulated granulocytes showed a biphasic alkaline elution pattern while fragmentation induced by alkylation or by enzymically produced O2- was monophasic. (b) Poly(ADP-ribosyl)ation of nuclear proteins after treatment with TPA-stimulated granulocytes exhibited a lag phase and was, in most experiments, less pronounced than after equitoxic dimethyl sulfate treatment. (c) 3–Aminobenzamide, the most widely used inhibitor of ADP-ribosylation, partially protected target cells from the cytotoxic effects of TPA-stimulated granulocytes, while it enhanced alkylation-induced and O2(-)-induced cytotoxicity. Protection by 3–Aminobenzamide in the granulocyte system was apparently not mediated by an inhibition of nuclear poly(ADP-ribosyl)ation. Other inhibitors, like benzamide and nicotinamide, augmented cytotoxicity of TPA-stimulated granulocytes. The unique effect of 3–Aminobenzamide in this system appeared to relate to TPA-induced adhesion of the neutrophils to surfaces. In the presence of 1 mM 3–Aminobenzamide, but not of benzamide, the adhesion of stimulated granulocytes to 3T3 monolayer cultures was markedly reduced or even abolished. This effect was also seen in granulocyte preparations depleted of monocytes. Since 3–Aminobenzamide at the doses applied does not inhibit TPA-induced superoxide production in isolated granulocytes, its specific anticytotoxic effect appears to result from a ‘dilution’ of granulocyte-derived damaging agents into the medium. Our data suggest that prevention of granulocyte adhesion is likely to reduce tissue damage and carcinogenesis in areas of chronic inflinflammation.
Peter Zahradka – One of the best experts on this subject based on the ideXlab platform.
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Repression of phosphoenolpyruvate carboxykinase gene activity by insulin is blocked by 3‐Aminobenzamide but not by PD128763, a selective inhibitor of poly(ADP‐ribose) polymerase
European journal of biochemistry, 1998Co-Authors: Lorraine Yau, Tracy Elliot, Chantal Lalonde, Peter ZahradkaAbstract:Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is induced by 3–Aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase. Synthesis of PEPCK mRNA is repressed by insulin, but remains detectable in H4IIE hepatoma cells exposed simultaneously to both 3–Aminobenzamide and insulin. This capability of 3–Aminobenzamide to block the inhibitory actions of insulin suggests that ADP-ribosylation is required for the regulation of PEPCK gene expression by insulin. Furthermore, neither changes in chromatin condcondensation nor cell growth status were linked to these events. The inability of 3,4-dihydro-5-methylisoquinolinone (PD128763), a selective inhibitor of poly(ADP-ribose) polymerase, to impede insulin-dependent repression of PEPCK gene expression, however, indicated that 3–Aminobenzamide does not operate by inhibiting poly(ADP-ribosyl)ation. The potential involvement of mono(ADP-ribosyl)ation, a process that is also inhibited by 3–Aminobenzamide, in the regulation of PEPCK gene activity was then evaluated. Analysis of poly(ADP-ribose) polymerase activity and poly(ADP-ribosyl)ation confirmed that there were no significant changes in response to insulin, while microsomal mono(ADP-ribosyl)transferase activity was elevated approximately fourfold. An increase in protein hydroxylamine-sensitive mono(ADP-ribosyl)ation was observed following insulin treatment. The sensitivity of the mono(ADP-ribosyl)transferase activity to 3–Aminobenzamide but not PD128763 makes it plausible that mono(ADP-ribosyl)ation rather than poly(ADP-ribosyl)ation contributes to the regulation of PEPCK gene expression.
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repression of phosphoenolpyruvate carboxykinase gene activity by insulin is blocked by 3 Aminobenzamide but not by pd128763 a selective inhibitor of poly adp ribose polymerase
FEBS Journal, 1998Co-Authors: Lorraine Yau, Peter Zahradka, Tracy Elliot, Chantal LalondeAbstract:Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is induced by 3–Aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase. Synthesis of PEPCK mRNA is repressed by insulin, but remains detectable in H4IIE hepatoma cells exposed simultaneously to both 3–Aminobenzamide and insulin. This capability of 3–Aminobenzamide to block the inhibitory actions of insulin suggests that ADP-ribosylation is required for the regulation of PEPCK gene expression by insulin. Furthermore, neither changes in chromatin condcondensation nor cell growth status were linked to these events. The inability of 3,4-dihydro-5-methylisoquinolinone (PD128763), a selective inhibitor of poly(ADP-ribose) polymerase, to impede insulin-dependent repression of PEPCK gene expression, however, indicated that 3–Aminobenzamide does not operate by inhibiting poly(ADP-ribosyl)ation. The potential involvement of mono(ADP-ribosyl)ation, a process that is also inhibited by 3–Aminobenzamide, in the regulation of PEPCK gene activity was then evaluated. Analysis of poly(ADP-ribose) polymerase activity and poly(ADP-ribosyl)ation confirmed that there were no significant changes in response to insulin, while microsomal mono(ADP-ribosyl)transferase activity was elevated approximately fourfold. An increase in protein hydroxylamine-sensitive mono(ADP-ribosyl)ation was observed following insulin treatment. The sensitivity of the mono(ADP-ribosyl)transferase activity to 3–Aminobenzamide but not PD128763 makes it plausible that mono(ADP-ribosyl)ation rather than poly(ADP-ribosyl)ation contributes to the regulation of PEPCK gene expression.
Robert T. Johnson – One of the best experts on this subject based on the ideXlab platform.
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Abnormal sister-chromatid exchange induction by 3–Aminobenzamide in an SV40-transformed Indianamuntaj cell:line: Relationships with DNA maturation and DNA-strand breakage
Mutation research, 1991Co-Authors: Bhavanath Jha, Simon D. Bouffler, C. Stephen Downes, Robert T. JohnsonAbstract:In SVM cells, an SV40-transformed line of Indian muntjac fibroblasts, levels of sister-chromatid exchanges are known to be abnormally high after UV-irradiation or alkylation. The SVM line is also known to have a defect in the processing of DNA-strand breaks. Sister-chromatid exchange in other cells is known to be stimulated by the poly(ADP-ribose) transferase inhibitor, 3–Aminobenzamide, which also retards DNA-break sealing. Sister-chromatid exchanges in SVM cells are found to be hypersensitive to 3–Aminobenzamide, or to nicotinamide deprivation which similarly inhibits poly(ADP-ribosyl)ation; DNA-strand breaks are likewise induced by 3–Aminobenzamide. Bromodeoxyuridine, needed to detect sister-chromatid exchanges, is more toxic to SVM cells and itself induces sister-chromatid exchanges to a greater extent than it does in normal muntjac cells. However, in contrast to the situation reported for other cell types prone to sister-chromatid exchange (the Chinese hamster ovary mutant EM9 and human Bloom’s Syndrome cells), SVM cells do not show an abnormal delay in DNA maturation when, under the influence of bromodeoxyuridine and 3–Aminobenzamide, they show a high level of sister-chromatid exchange. The mechanism by which BrdU exerts its effects can largely be explained in terms of familiar effects on deoxyribonucleotide pools and DNA integrity. 3–Aminobenzamide, however, induces sister-chromatid exchanges in SVM cells by another mechanism.
Thomas Meyer – One of the best experts on this subject based on the ideXlab platform.
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3‐Aminobenzamide inhibits cytotoxicity and adhesion of phorbol‐ester‐stimulated granulocytes to fibroblast monolayer cultures
European journal of biochemistry, 1991Co-Authors: Thomas Meyer, Helgard Lengyel, Werner Fanick, Helmuth HilzAbstract:Damage of 3T3 fibroblasts as induced by short-term co-cultivation with O2(-)-producing granulocytes, stimulated by 12-O-tetradecanoyl-phorbol-13-acetate (TPA), was compared with that induced by treatment with enzymically generated O2- and with the alkylating agent dimethyl sulfate. The action of stimulated granulocytes was different in several aspects: (a) DNA fragmented by the products of TPA-stimulated granulocytes showed a biphasic alkaline elution pattern while fragmentation induced by alkylation or by enzymically produced O2- was monophasic. (b) Poly(ADP-ribosyl)ation of nuclear proteins after treatment with TPA-stimulated granulocytes exhibited a lag phase and was, in most experiments, less pronounced than after equitoxic dimethyl sulfate treatment. (c) 3–Aminobenzamide, the most widely used inhibitor of ADP-ribosylation, partially protected target cells from the cytotoxic effects of TPA-stimulated granulocytes, while it enhanced alkylation-induced and O2(-)-induced cytotoxicity. Protection by 3–Aminobenzamide in the granulocyte system was apparently not mediated by an inhibition of nuclear poly(ADP-ribosyl)ation. Other inhibitors, like benzamide and nicotinamide, augmented cytotoxicity of TPA-stimulated granulocytes. The unique effect of 3–Aminobenzamide in this system appeared to relate to TPA-induced adhesion of the neutrophils to surfaces. In the presence of 1 mM 3–Aminobenzamide, but not of benzamide, the adhesion of stimulated granulocytes to 3T3 monolayer cultures was markedly reduced or even abolished. This effect was also seen in granulocyte preparations depleted of monocytes. Since 3–Aminobenzamide at the doses applied does not inhibit TPA-induced superoxide production in isolated granulocytes, its specific anticytotoxic effect appears to result from a ‘dilution’ of granulocyte-derived damaging agents into the medium. Our data suggest that prevention of granulocyte adhesion is likely to reduce tissue damage and carcinogenesis in areas of chronic inflammation.
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3 Aminobenzamide inhibits cytotoxicity and adhesion of phorbol ester stimulated granulocytes to fibroblast monolayer cultures
FEBS Journal, 1991Co-Authors: Thomas Meyer, Helgard Lengyel, Werner Fanick, Helmuth HilzAbstract:Damage of 3T3 fibroblasts as induced by short-term co-cultivation with O2(-)-producing granulocytes, stimulated by 12-O-tetradecanoyl-phorbol-13-acetate (TPA), was compared with that induced by treatment with enzymically generated O2- and with the alkylating agent dimethyl sulfate. The action of stimulated granulocytes was different in several aspects: (a) DNA fragmented by the products of TPA-stimulated granulocytes showed a biphasic alkaline elution pattern while fragmentation induced by alkylation or by enzymically produced O2- was monophasic. (b) Poly(ADP-ribosyl)ation of nuclear proteins after treatment with TPA-stimulated granulocytes exhibited a lag phase and was, in most experiments, less pronounced than after equitoxic dimethyl sulfate treatment. (c) 3–Aminobenzamide, the most widely used inhibitor of ADP-ribosylation, partially protected target cells from the cytotoxic effects of TPA-stimulated granulocytes, while it enhanced alkylation-induced and O2(-)-induced cytotoxicity. Protection by 3–Aminobenzamide in the granulocyte system was apparently not mediated by an inhibition of nuclear poly(ADP-ribosyl)ation. Other inhibitors, like benzamide and nicotinamide, augmented cytotoxicity of TPA-stimulated granulocytes. The unique effect of 3–Aminobenzamide in this system appeared to relate to TPA-induced adhesion of the neutrophils to surfaces. In the presence of 1 mM 3–Aminobenzamide, but not of benzamide, the adhesion of stimulated granulocytes to 3T3 monolayer cultures was markedly reduced or even abolished. This effect was also seen in granulocyte preparations depleted of monocytes. Since 3–Aminobenzamide at the doses applied does not inhibit TPA-induced superoxide production in isolated granulocytes, its specific anticytotoxic effect appears to result from a ‘dilution’ of granulocyte-derived damaging agents into the medium. Our data suggest that prevention of granulocyte adhesion is likely to reduce tissue damage and carcinogenesis in areas of chronic inflammation.